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Article dans une revue Cell Host and Microbe Année : 2018

Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer

Mauro S. Malnati
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Résumé

The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry. Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1 Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization provides a widely applicable template for the design of Env-based HIV-1 vaccines.
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Dates et versions

hal-02531048, version 1 (14-12-2023)

Identifiants

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Peng Zhang, Jason Gorman, Hui Geng, Qingbo Liu, Yin Lin, et al.. Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer. Cell Host and Microbe, 2018, 23 (6), pp.832-844.e6. ⟨10.1016/j.chom.2018.05.002⟩. ⟨hal-02531048⟩
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